CZ172596A3 - PROCESS FOR PREPARING SUBSTITUTED HEXAHYDRO-2N-CYCLOPENTA/b/FURAN-2-ONES - Google Patents

Abstract

In the present invention there is disclosed a process for preparing substituted hexahydro-2H-cyclopenta/b/furan-2-ones of the general formula I, in which A represents hydrogen, B represents a hydroxyl group or A together with B form an ethylenedioxyl bridge, R represents alkyl containing 1 to 6 carbon atoms being optionally branched or a phenoxyl group being optionally substituted with a halogen or a haloalkyl group containing 1 to 2 carbon atoms in the alkyl moiety, particularly 3-chlorophenoxyl or 3-trifluoromethylphenoxyl group. The proposed preparation process is characterized by transesterification of starting lactone esters of the general formula II, in which A, B, R and Ph are as specified above in anhydrous methanol and in the presence of alkali metal alkyloxides as catalysts at a temperature ranging from 20 to 65 degC for a period of 1 to 6 hours, whereby after crystallization of methyl-p-phenyl benzoate the required hydroxy derivative of the general formula I in actually quantitative yield and high purity is obtained.

Description

A process for the preparation of substituted hexahydro-2H-cyclopenta [b] furan-2-ones

Area of tangents

The present invention relates to a process for the preparation of substituted hexahydro-2H-cyclopenta (b) furan-2-ones of formula (I),

wherein A represents hydrogen, B represents hydroxyl or A together with B forms an ethylenedioxyl bridge, R represents alkyl of 1 to 6 carbon atoms optionally branched or phenoxy optionally substituted by halogen or haloalkyl, in particular 3-chlorophenoxy or 3-trifluoromethylenenoxy.

These compounds are important intermediates in prostaglandin synthesis.

BACKGROUND OF THE INVENTION

Natural prostaglandins and their versatile use in their synthetic analogues have been found in human and veterinary medicine by, for example, W. D. Prostaglandine J. Mares et al.

a wide range of biological effects. They are used to treat cardiovascular, gastrointestinal, gynecological, urological, ophthalmological and other diseases as well as to control oestrus and induction of labor in livestock (see Watkins, B. Peterson, J. R. Fletcher (Eds):

in Clinical Practice, Raven Press, N.Y., 1989, Biol.Chem.Vet. (Prague), XXVII (XXXII), 385 (1990).

For the preparation of prostaglandins, the use of intermediates of formula I is well known (DOS No. 2,234,708, No. 2,234,709, British Pat.

438 093, MS. U.S. Pat. No. 192 456, MS. AO 201,027, AO 246,783). The above processes use generally potash in methanol to remove the acyl (p-phenylbenzoyl) protecting group from the precursor of formula (II), the amount of catalyst used often being up to its equivalent. A disadvantage of the application of this agent is also the fact that the lactone ring opening of the product of the general formula (I) is more reversible, so that after the transesterification, the mixture must first be acidified and additionally neutralized again. This increases the amount of waste inorganic salts and complicates the isolation of the reaction product. This is usually isolated by chromatography or after trituration removal of the by-product methyl 1-p-phenylbenzoate by crystallization of the trituration residue from a suitable organic solvent. Chromatographic and possibly crystallization isolation of the product, if it is crystalline, provides very pure products, but especially the former is technically demanding, requiring expensive processing equipment and the use of other auxiliary raw materials (sorbent, chromatographic solvents), while the crystallization process is associated with certain losses in the mother liquors after crystallization, unless they are further processed.

These processes are followed in a positive way by the process according to the invention, which works with inexpensive and available raw materials, simplifying the isolation of the reaction product, which is moreover virtually lossless. The method used is technologically safe and environmentally friendly.

The essence of the invention

The process according to the invention consists in carrying out the transesterification of the starting lactonesters of formula II, in which A, B and R are as defined above in anhydrous methanol in the presence of alkali metal alcoholates, which are highly efficient catalysts of the reaction. Virtually complete conversion is achieved within 1 to 6 hours even at low catalyst concentrations, which are typically in the range of 2 to 20 mol%. The reaction can be carried out at temperatures from 20 ° C to the boiling point of the mixture (about 65 ° C). Suitable alkocholates are sodium and potassium alkoxides of C 1 -C 4 -alcohols, namely sodium methoxide or a target. potassium butoxide. In the catalysis of alcoholates, undesirable side reactions, such as ex. hydrolytic. opening of the lactone ring, which is common when potash is used. The progress of the reaction can be easily monitored by TLC analysis. After completion of the reaction and partial cooling of the mixture, the catalyst is neutralized by the addition of a mineral acid, preferably diluted with methanol, or by successive addition of excess solid carbon dioxide. A suitable mineral acid is sulfuric or hydrochloric acid. The reaction mixture is further cooled to -20 to -30 ° C where a substantial amount of methyl p-phenylbenzoate crystallizes, which is removed by filtration or centrifugation, the solid phase is washed with cold methanol and the combined filtrates are partially concentrated on a rotary evaporator. The concentrate is again subjected to low-temperature crystallization separation of methyl p-phenylbenzoate in an analogous manner, after which the filtrate obtained is freed from the solvent by evaporation on a rotary evaporator. This gives the desired hydroxy derivative of the general formula I, wherein A, B and R have the previously mentioned meaning, practically in quantitative yield and purity suitable for further processing, which can be further increased if necessary by simple chromatographic purification.

A specific embodiment of the process according to the invention is given in the following examples, which are illustrative and in no way limit the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1.

To a solution of 20 g of the levorotatory antipode of the lactonester of formula I (A is hydrogen, B is hydroxyl, R is n-butyl) in 100 ml of dry methanol is added 6 ml of 1M methanolic sodium methoxide solution and stirred The reaction was complete by TLC analysis (silica gel, dichloromethane + 10% methanol). The reaction mixture is cooled to 30 ° C and neutralized by addition of approximately 2.5 ml of a 20% methanolic sulfuric acid solution to pH = 4-5 when the pH meter electrode is introduced.

The contents of the baft are cooled to -20 to -25 ° C and after 2 hours the crystalline fraction is filtered on a frit. The cake was washed with 2 x 20 mL cold methanol and the combined filtrates were concentrated to 50g. The residue is recooled to -25 to -30 ° C for 12 hours, the solid phase is drained vigorously, washed with 2 x 5 ml cold methanol and the combined filtrates are evaporated on a rotary evaporator at a bath temperature of up to 65 ° C and a pressure below 2 ° C. 5 kPa to constant weight. This gives approximately 12.5 g of the hydroxy derivative of the formula I (A, B and R as defined above) in the form of a viscous honey having a content of 92% (HPLC) and chromatographically identical to an authentic sample (Rf = 0.35, plate). Merck GF 254 (10% methanol in dichloromethane).

Example 2.

To a solution of 0.5 <3 racemic lactonester of formula II (A stands for hydrogen, B stands for hydroxyl function and R stands for 3-chlorophenoxy group) in 45 ml of dry methanol is added 0.76 ml of a 1.8 M solution of potassium tert-butoxide in tetrahydrofuran . The mixture was stirred at 50 ° C for 4 hours, then cooled to 25 ° C and neutralized by addition of concentrated hydrochloric acid to pH = 4 to 4.5 using a pH meter. The solution is concentrated to a volume of 5 ml and left at -25 ° C for 12 hours. The crystalline fraction was filtered off and the filtrate was evaporated on a rotary evaporator at 55 ° C to constant weight. This gives 0.42 <3 hydroxy derivative of formula I (A, B, and R is as defined above) in a purity of 74% (HPLC), which by chromatographic analysis is identical to the authentic specimen (R _f = 0.38, plate Mercks54 10% methanol in dichloromethane).

Example 3.

To a solution of the 4.2 <3 racemic lactonester of formula II (A together with B forms an ethylenedioxyl bridge, R stands for a 3-chlorophenoxy group) in 40 ml of dry methanol is added 1.2 ml of a 1.2 M solution of sodium methoxide in methanol, and The reaction mixture is cooled to 30 ° C in portions of about 10 < 3 &gt; solid carbon dioxide in coarser pieces. After gas evolution had ceased, the cooled mixture was further maintained at -25 to -30 ° C for 3 hours. The precipitated crystalline phase is filtered off with suction, washed with 4 ml of cold methanol and the combined filtrates are concentrated on a rotary evaporator to a volume of 10 ml. The solution was recooled to -25 to -30 ° C and left overnight. The crystalline fraction was vigorously filtered off with suction, washed with 3 ml of methanol and the combined filtrates were evaporated on a evaporator at a bath temperature of 55 ° C. 2.8 g of a residue was obtained which was identical (TLC silica gel, dichloromethane + 5% methanol,

Rf = 0.55) with authentic product.

Claims (5)

Patent claims A process for the preparation of substituted hexahydro-2H-cyclopenta [b] furan-2-ones of formula I wherein A is hydrogen, B is hydroxyl or A together with B forms an ethylenedioxyl bridge, R is alkyl of 1 to 8 or phenoxy or a haloalkyl carbon atom optionally branched with an optionally substituted halogen group, in particular a 3-chlorophenoxy or 3-trifluoromethylphenoxy group, characterized in that the solutions of the lactonesters of formula II, where A, B, R are as defined above, are treated with alkali alcoholates in dry methanol metal at 20 to 65 ° C for 1 to δ hours, after transesterification the catalyst is neutralized, the reaction mixture is cooled to -10 to -30 ° C, the methyl-p-phenylbenzoate precipitated is separated by filtration or centrifugation, the filtrate is evaporated it is freed from the solvent under vacuum to give the product of formula I (A, B, R as defined above), which is: possibly refining further. 2. A process according to claim 1, wherein the alkali metal alcoholates are sodium or potassium alkoxides of C1 -C4 alcohols, preferably sodium methoxide or potassium tert-butoxide, wherein the amount of alkoxide relative to the substrate is in the range of 2 to 4 carbon atoms. up to 20 mol%. 3. Process according to claim 1, characterized in that the neutralization is carried out with mineral acids or solid carbon dioxide, with methanolic sulfuric or hydrochloric acid being particularly preferred. 4. A process according to claim 1, wherein the starting material of the formula II used can be in racemic or optically active form. « 5. The process according to claim 1, wherein the optional further refining of the product is carried out by repeatedly crystallizing removal of methyl p-phenylbenzoate from the concentrated filtrate after the first separation step, or refining is completed by column chromatography according to generally known procedures.